Differential Antigenotoxic and Cytoprotective effect of Amifostine in Idarubicin-Treated mice

MARCELO DE CAMPOS NEBEL, IRENE LARRIPA, MARCELA GONZÁLEZ-CID

ENVIRONMENTAL AND MOLECULAR MUTAGENESIS

Wiley-Liss, Inc.

Año: 2002 vol. 39 p. 3 - 9

0893-6692

In this study we evaluated the antigenotoxic and cytoprotective capabilities of WR-2721[S-2-(3-aminopropylamino)- ethylphosphorothioic acid (amifostine)] in different normal tissues of BALB/c mice treated with idarubicin [4-demethoxydaunorubicin (IDA)]. The aminothiol WR-2721 is a pro-drug that requires dephosphorylation to its active metabolite WR-1065, to produce selectively cytoprotective activity in normal tissues exposed to radio- and chemotherapeutic agents, without protecting malignant tissues. IDA is an effective chemotherapeutic agent against hematological diseases, but produces a broad spectrum of toxicity in nontumoral cells. Animals were injected intravenously with WR-2721 (250 mg/kg) or IDA (6 mg/kg) and WR-2721/IDA. Micronuclei frequency in bone marrow was measured 24 and 48 hr after initiation of the treatments. The IDA-treated group showed increased levels of micronuclei. However, the WR-2721- and WR-2721/IDA-treated groups did not show differences from the controls. Genetic damage was evaluated by alkaline single-cell gel electrophoresis at 24-hr posttreatments. Important DNA damage was observed in liver, spleen, and peripheral blood cells of mice treated with IDA. The presence of WR-2721 diminished that damaging effect only in liver cells. The apoptotic index was measured in liver and spleen tissues by the TUNEL assay 14 and 24 hr after treatment. In liver we observed an increased percentage of apoptotic cells at 24 hr for the IDA-treated group, whereas the WR-2721 and WR-2721/IDA groups remained at low levels. Splenic cells treated with IDA and WR-2721/IDA showed increased DNA fragmentation levels at any time. In conclusion, WR-2721 has a tissue-specific antigenotoxic and cytoprotective effect in IDA-treated mice using these experimental conditions. Environ. Mol. Mutagen. 39:3–9, 2002. © 2002 Wiley-Liss, Inc.S-2-(3-aminopropylamino)- ethylphosphorothioic acid (amifostine)] in different normal tissues of BALB/c mice treated with idarubicin [4-demethoxydaunorubicin (IDA)]. The aminothiol WR-2721 is a pro-drug that requires dephosphorylation to its active metabolite WR-1065, to produce selectively cytoprotective activity in normal tissues exposed to radio- and chemotherapeutic agents, without protecting malignant tissues. IDA is an effective chemotherapeutic agent against hematological diseases, but produces a broad spectrum of toxicity in nontumoral cells. Animals were injected intravenously with WR-2721 (250 mg/kg) or IDA (6 mg/kg) and WR-2721/IDA. Micronuclei frequency in bone marrow was measured 24 and 48 hr after initiation of the treatments. The IDA-treated group showed increased levels of micronuclei. However, the WR-2721- and WR-2721/IDA-treated groups did not show differences from the controls. Genetic damage was evaluated by alkaline single-cell gel electrophoresis at 24-hr posttreatments. Important DNA damage was observed in liver, spleen, and peripheral blood cells of mice treated with IDA. The presence of WR-2721 diminished that damaging effect only in liver cells. The apoptotic index was measured in liver and spleen tissues by the TUNEL assay 14 and 24 hr after treatment. In liver we observed an increased percentage of apoptotic cells at 24 hr for the IDA-treated group, whereas the WR-2721 and WR-2721/IDA groups remained at low levels. Splenic cells treated with IDA and WR-2721/IDA showed increased DNA fragmentation levels at any time. In conclusion, WR-2721 has a tissue-specific antigenotoxic and cytoprotective effect in IDA-treated mice using these experimental conditions. Environ. Mol. Mutagen. 39:3–9, 2002. © 2002 Wiley-Liss, Inc.